Despite the high prevalence of venous diseases that are associated with and based on the structural reorganization of the venous vessel wall, not much is known about their mechanistic causes. In this context, we demonstrated that the quantity of myocardin, a transcriptional regulator of the contractile and quiescent smooth muscle cell phenotype, was diminished in proliferating synthetic venous smooth muscle cells (VSMCs) of human and mouse varicose veins by 51 and 60%, respectively. On the basis of the relevance of proteasomal activity for such phenotypic changes, we hypothesized that the observed VSMC activation is attenuated by the proteasome inhibitor bortezomib. This drug fully abolished VSMC proliferation and loss of myocardin in perfused mouse veins and blocked VSMC invasion in collagen gels by almost 80%. In line with this, topical transdermal treatment with bortezomib diminished VSMC proliferation by 80%, rescued 90% of VSMC myocardin abundance, and inhibited varicose-like venous remodeling by 67 to 72% in a mouse model. Collectively, our data indicate that the proteasome plays a pivotal role in VSMC phenotype changes during venous remodeling processes. Its inhibition protects from varicose-like vein remodeling in mice and may thus serve as a putative therapeutic strategy to treat human varicose veins.

BackgroundDespite the high prevalence of chronic venous insufficiency and varicose veins in the Western world, suitable pharmaceutical therapies for these venous diseases have not been explored to date. In this context, we recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins through the activation of the transcription factor activator protein 1.Methods and ResultsWe investigated whether deleterious venous remodeling is suppressed by the pleiotropic effects of statins. In vitro, activator protein 1 activity was inhibited by two 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, rosuvastatin and atorvastatin, in stretch‐stimulated human venous smooth muscle cells. Correspondingly, both statins inhibited venous smooth muscle cell proliferation as well as mRNA expression of the activator protein 1 target gene monocyte chemotactic protein 1 (MCP1). In isolated mouse veins exposed to an increased level of intraluminal pressure, statin treatment diminished proliferation of venous smooth muscle cells and protein abundance of MCP1 while suppressing the development of varicose veins in a corresponding animal model by almost 80%. Further analyses of human varicose vein samples from patients chronically treated with statins indicated a decrease in venous smooth muscle cell proliferation and MCP1 abundance compared with samples from untreated patients.ConclusionsOur findings imply that both atorvastatin and rosuvastatin effectively inhibit the development of varicose veins, at least partially, by interfering with wall stress–mediated activator protein 1 activity in venous smooth muscle cells. For the first time, this study reveals a potential pharmacological treatment option that may be suitable to prevent growth of varicose veins and to limit formation of recurrence after varicose vein surgery.

Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context – a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

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ZusammenfassungEinleitung: Trotz ihrer Bedeutung für beinahe ein Drittel der erwachsenen Bevölkerung in den Industrienationen ist nur wenig über die Mechanismen, die eine gesunde Vene in eine Varize transformieren, bekannt. Epidemiologisch und ätiologisch ist nachgewiesen, dass viele Risikofaktoren, welche die Spannung der Venenwand vergrößern – wie stehendes Arbeiten oder eine Adipositas-bedingte Erhö-hung des Venendrucks – auch die Wahrscheinlichkeit für eine Varikosis bzw. chronische venöse Insuffizienz (CVI) erhöhen.Methodik und Ergebnisse: Vor diesem Hinter-grund wurde mit Hilfe der Ligation einer Ohrmuschelvene der Maus der Venendruck lokal erhöht und venöse Remodellierungsprozesse induziert. Auf Basis dieses neuartigen Mausmodells konnten wir kürzlich zeigen, dass die Steigerung der Wandspannung venöse Endothel- und glatte Muskelzellen aktiviert, und konsekutiv den varikösen Umbau der Venen-wand initiiert.Schlussfolgerung: Unsere Ergebnisse deuten darauf hin, dass eine erhöhte venöse Wand-spannung ausreichend ist, um Varikosis zu initiieren und zu fördern. In diesem Artikel versuchen wir diese durch die Laplace-Beziehung beschriebene biomechanische Kraft etwas nä-her zu beleuchten, und erläutern wie die Wandspannung die verschiedenen Varikosisassoziierten Wandumbauprozesse und deren Behandlungsstrategien beeinflussen kann.